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Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents

What to Start: Initial Combination Regimens for the Antiretroviral-Naive Patient

The optimal antiretroviral (ARV) regimen for a treatment-naive patient consists of two NRTIs in combination with a third active ARV drug from one of three drug classes: an NNRTI, a PI boosted with ritonavir, or an INSTI (AI).

The Panel recommends one of the following regimens for ART-naive patients regardless of baseline viral load or CD4 count:

NNRTI-Based Regimen:

EFV/TDF/FTCa (AI)

PI-Based Regimens:

ATV/r plus TDF/FTCa (AI)

DRV/r plus TDF/FTCa (AI)

INSTI-Based Regimens:

DTG plus ABC/3TCa (AI)—only for patients who are HLA-B*5701 negative

DTG plus TDF/FTCa (AI)

EVG/cobi/TDF/FTC—onlyfor patients with pre-ART CrCl >70 mL/min (AI)

RAL plus TDF/FTCa (AI)

In addition to the regimens listed above, the following regimens are also recommended, but only for patients with pre-ART plasma HIV RNA <100,000 copies/mL:

NNRTI-Based Regimens:

EFV plus ABC/3TCa (AI)—only for patients who are HLA-B*5701 negative

RPV/TDF/FTCa (AI)—only for patients with CD4 count >200 cells/mm3

PI-Based Regimen:

ATV/r plus ABC/3TCa (AI)–only for patients who are HLA-B*5701 negative

On the basis of individual patient characteristics and needs, an Alternative Regimen may in some instances be the optimal regimen for a patient. A list of Alternative Regimens can be found in Table 6.

The optimal initial ARV regimen for a treatment-naive patient consists of two NRTIs in combination with a drug from one of three drug classes: an NNRTI, a PI boosted with ritonavir (RTV), or an INSTI. As shown in clinical trials and by retrospective evaluation of cohorts of patients in clinical care, this strategy has resulted in HIV RNA decreases and CD4 T lymphocyte (CD4) cell increases in most patients.1,2

Since 2009, the Panel has listed four regimens as “Preferred” for initial therapy of HIV infection: the NRTI combination tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) with one of the following: efavirenz (EFV), ritonavir-boosted atazanavir (ATV/r) or ritonavir-boosted darunavir (DRV/r), or raltegravir (RAL). Subsequently, the FDA has approved several new agents and co-formulated products for treatment-naive individuals on the basis of data from randomized clinical trials that compared regimens containing the newer drugs to one of the four preferred regimens. On the basis of this data, as well as from long-term follow-up of these studies and experience in clinical practice, the Panel recognizes that options for initial therapy have expanded. Consequently, the Panel now refers to these options for initial treatment as "Recommended" rather than "Preferred" regimens.

The revised Table 6 lists Recommended and Alternative initial options for HIV treatment. The table also lists additional regimens that may be recommended for patients with pre-treatment plasma viral load <100,000 copies/mL. Each of the options listed has demonstrated favorable antiviral efficacy, safety, and tolerability in comparative clinical trials. The list of Alternative regimens has been shortened because with more Recommended options, clinicians should be able to choose a Recommended regimen for most treatment-nave patients. The Alternative regimens listed are effective and tolerable but, when compared with Recommended options, have potential disadvantages or less data supporting their use.

Previous versions of these Guidelines listed several options for initial therapy that included ARV agents that are less effective, less convenient, and/or more toxic than current options—specifically, zidovudine (ZDV), nevirapine (NVP), ritonavir-boosted saquinavir (SQV/r), ritonavir-boosted fosamprenavir (FPV/r), unboosted atazanavir (ATV), and maraviroc (MVC). Given that many better options are now available, the panel no longer considers the components listed as suitable agents for initial treatment.

Aside from the change in terminology from "Preferred" to “Recommended" regimens, the major additions to the list of options for initial treatment are the inclusion of the following INSTI-based options as Recommended regimens (regardless of pre-treatment HIV RNA):

Dolutegravir (DTG) plus abacavir/lamivudine (ABC/3TC) or TDF/FTC (AI)

Elvitegravir (EVG)/cobicistat (cobi)/TDF/FTC (AI)

Additionally, the following three regimens are now listed as Recommended regimens, but only for patients with pre-treatment HIV RNA level <100,000 copies/mL:

EFV plus ABC/3TC (AI)

Rilpivirine (RPV)/TDF/FTC (and if CD4cell count >200 cells/mm3) (AI)

ATV/r plus ABC/3TC (AI)

The change in classification of EVG/cobi/TDF/FTC and RPV/TDF/FTC regimens is based on additional efficacy and safety data. DTG, when given once daily in combination with two NRTIs (TDF/FTC or ABC/3TC), has demonstrated non-inferiority to RAL and superiority to both EFV and DRV/r. These newer options are reviewed in greater detail below.
Data Used for Making Recommendations

The Panel’s recommendations are primarily based on clinical trial data published in peer-reviewed journals and data prepared by manufacturers for FDA review. In select cases, the Panel considers data presented in abstract format at major scientific meetings. The first criterion for selection of evidence on which to base recommendations is published information from a randomized, prospective clinical trial with an adequate sample size that demonstrates that an ARV regimen has shown durable viral suppression, increased CD4 cell count, and has a favorable safety profile. Comparative clinical trials of initial treatments generally show no significant differences in HIV-related clinical endpoints or survival. Thus, assessment of regimen efficacy and safety are primarily based on surrogate marker endpoints (especially rates of HIV RNA suppression) and the incidence and severity of adverse events.

The Panel reviewed data from randomized clinical trials and other reports to arrive at “Recommended” or “Alternative” regimens, as specified in Table 6. “Recommended regimens” are those studied in randomized controlled trials and shown to have optimal and durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. “Alternative regimens” are those that are effective but have potential disadvantages or fewer data than “Recommended regimens.” In certain situations and depending on individual patient characteristics and needs, a regimen listed as an Alternative may actually be the optimal regimen for a specific patient.
Considerations When Selecting A Regimen for Antiretroviral Therapy-Naive Patients

Factors to Consider When Selecting an Initial Regimen

Regimen selection should be individualized on the basis of a variety of factors, including the following:

Each of the recommended initial regimens listed in Table 6 has shown potent virologic efficacy as measured by the proportion of participants in comparative clinical trials able to achieve and maintain viral suppression. On the basis of study results, some of the regimens are recommended for patients regardless of pre-treatment HIV RNA level whereas others are recommended only for patients whose baseline HIV RNA is <100,000 copies/mL.

Recommended regimens for initial treatment include two NRTIs combined with a third agent: an NNRTI, a ritonavir-boosted PI, or an INSTI.
Choosing a Nucleoside Reverse Transcriptase Inhibitor Combination

Recommended regimens include the NRTI combination of TDF/FTC or ABC/3TC; both are available as fixed-dose combination tablets and are dosed once daily. One consideration when choosing between these NRTI combinations is virologic efficacy. A large randomized trial comparing TDF/FTC and ABC/3TC—each combined with either ATV/r or EFV—found that TDF/FTC resulted in better virologic responses than ABC/3TC in participants with pre-treatment HIV RNA levels ≥100,000 copies/mL; this difference was not seen in patients with HIV RNA <100,000 copies/mL.3 Another study comparing TDF/FTC and ABC/3TC, each combined with ritonavir-boosted lopinavir (LPV/r), did not find differences in virologic efficacy between the NRTI pairs.4 In the SINGLE trial, in which DTG plus ABC/3TC was compared to EFV/TDF/FTC, there was no difference in virologic responses between TDF/FTC and ABC/3TC in patients with high HIV RNA levels.5 Potential adverse events are another consideration when choosing between these NRTI combinations. TDF can cause nephrotoxicity, particularly in patients who have pre-existing renal disease or risk factors for kidney disease (e.g., use of other nephrotoxic drugs) or in those receiving PIs. Patients who start TDF-containing regimens have a greater initial decrease in bone mineral density than those who start ABC-containing therapy, although bone density levels subsequently stabilize.

Before starting ABC, a patient must be tested for the HLA B*5701 allele, which predicts hypersensitivity to this drug. In the United States, approximately 8% of whites and 2.5% of African Americans are positive for this allele.6 Some observational studies have linked ABC to increased rates of myocardial infarction,7-9 but this finding has not been confirmed in all analyses of clinical trial data, including a meta-analysis conducted by the FDA.10

One final consideration in choosing an NRTI combination is hepatitis B coinfection. TDF/FTC is the preferred NRTI combination in patients who also have chronic hepatitis B because both agents have activity against HBV.

ZDV/3TC is no longer recommended for initial treatment of HIV infection in non-pregnant adults because it has more toxicities than TDF/FTC or ABC/3TC and requires twice daily dosing.
Choosing between a Non-Nucleoside Reverse Transcriptase Inhibitor, Protease Inhibitor, or Integrase Strand Transfer Inhibitor as the Third Drug in the Regimen

Factors influencing the choice between an NNRTI, PI or INSTI as the third drug in a regimen include efficacy, adverse effects, convenience (e.g., dosing frequency, number of pills, food requirements), genetic barrier to resistance, co-morbidities, concomitant medications, and potential for drug-drug interactions. All of the Recommended NNRTI-, PI- and INSTI-based regimens are potent, demonstrating high rates of virologic suppression in clinical trials. However, because lower virologic efficacy has been seen in patients with high baseline HIV RNA levels who received RPV- based regimen, it is recommended only in patients with HIV RNA levels <100,000 copies/mL. Some adverse events are specific to particular drugs within each drug class (see Table 7) and are an important consideration when selecting an initial regimen. In terms of convenience, once-daily single-pill combinations that contain all components of a regimen are currently available for TDF/FTC plus an NNRTI (EFV or RPV) or an INSTI (EVG/cobi). Patients and clinicians often prefer these regimens because of their low pill burden and favorable dosing frequency.

In contrast, regimens that include PIs have a greater pill burden, typically 3 pills once a day. However, PIs have a high genetic barrier to resistance: multiple viral mutations are generally required to reduce the activity of agents in this class, and virologic failure rarely selects for PI-resistance. Consequently, some clinicians consider regimens that include PIs to be the initial regimens of choice for patients with suboptimal or unknown adherence and a higher risk for virologic failure. In addition, because transmitted drug resistance to PIs is relatively uncommon, drugs in the PI class are favored when a regimen is started before HIV resistance testing results are available (e.g., when treating acute HIV infection, including in those who became HIV infected while prescribed TDF/FTC for pre-exposure prophylaxis). However, PIs and cobi (a pharmaco-enhancer that increases EVG levels) are potent inhibitors of the cytochrome p450 pathway; therefore, regimens containing these drugs have a greater potential for drug-drug interactions than other combinations, which may be a disadvantage in patients who are receiving other medications that are primarily metabolized through this pathway.
Choosing Among Non-Nucleoside Reverse Transcriptase Inhibitor Options

Among the Recommended regimens, EFV in combination with TDF/FTC has been studied in the greatest number of clinical trials.11-16 This regimen, which also has extensive use in clinical practice, is available in a single tablet, once-daily formulation. In a large randomized trial comparing ABC/3TC plus EFV and TDF/FTC/EFV, ABC/3TC plus EFV showed inferior virologic responses in patients with pre-treatment HIV-1 RNA levels ≥100,000 copies/mL.3 On the basis of these results, TDF/FTC/EFV is a Recommended regimen regardless of HIV RNA level, whereas ABC/3TC plus EFV is a Recommended option only for patients with pretreatment HIV RNA levels <100,000 copies/mL. Disadvantages of EFV-containing regimens include central nervous system (CNS) side effects, which resolve or improve in some, but not all, patients; a higher incidence of rash (including severe skin reactions) than with other Recommended regimens; and dyslipidemia. Because of potential teratogenicity of EFV, regimens that do not include EFV should be considered in women who wish to conceive or are sexually active and not using contraception. A suppressive EFV-based regimen can be continued in pregnant women who present for antenatal care in the first trimester because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy, before pregnancy is usually recognized. EFV induces the cytochrome p450 pathway; therefore, regimens containing EFV have a potential for drug-drug interactions, which may be a disadvantage in those patients who are receiving other medications.

Studies comparing RPV to EFV, each in combination with two NRTIs, found equal rates of virologic suppression for the drugs. However, in patients with pre-therapy HIV RNA >100,000 copies/mL or CD4 count <200 cells/mm3, the rate of virologic failure was higher in patients who were randomized to RPV than to EFV.14

Therefore, RPV is a recommended option only when a patient’s pre-treatment HIV RNA is <100,000 copies/mL and CD4 count >200 cells/mm3. In these studies, RPV-containing regimens were better tolerated than EFV-containing combinations, and had fewer adverse lipid effects. RPV in combination with TDF/FTC is available as a single tablet, once daily formulation. RPV with ABC/3TC is not available in a single tablet formulation and has substantially less experience in clinical trials and practice than RPV/TDF/FTC. RPV must be taken with a meal. Because RPV requires stomach acid for absorption, it cannot be taken with proton pump inhibitors and should be used with caution (i.e., staggered dosing) in patients receiving H2 blockers or antacids.

Nevirapine (NVP) is no longer a Recommended or Alternative NNRTI because of greater toxicity and the availability of better options.
Choosing Among Protease Inhibitor Options

ATV/r is as effective as EFV, but causes fewer CNS side effects and less rash and has a more favorable lipid profile when used in combination with two NRTIs.13 One study found that among women enrolled in the study, those randomized to ATV/r had a lower virologic response rate than those randomized to EFV.17 ATV can cause reversible indirect hyperbilirubinemia, which may result in visible jaundice or scleral icterus in a small proportion of patients. ATV has also been associated with nephrolithiasis, nephrotoxicity, and cholelithiasis. Optimal absorption of ATV depends on the presence of food and low gastric pH; if acid-reducing agents are needed, ATV should be co-administered according to dosing guidelines shown in Table 18a. In the only randomized trial of ATV/r with either ABC/3TC or TDF/FTC, ABC/3TC showed an inferior response in patients with pre-treatment HIV RNA levels ≥100,000 copies/mL.3 Therefore, ATV/r plus TDF/FTC is a Recommended regimen regardless of HIV RNA, whereas ATV/r plus ABC/3TC is a Recommended option only for patients with pretreatment HIV RNA levels <100,000 copies/mL.

DRV/r shares many of the characteristics of boosted ATV, but does not cause hyperbilirubinemia, nephrolithiasis, nephrotoxicity, or cholelithiasis, and can be given with acid-reducing agents. Patients initiating DRV/r may develop a skin rash, which is usually mild to moderate in severity and self-limited. Rarely, severe rash with fever or elevated transaminase levels may occur, which necessitates discontinuation of the drug. There is more experience in clinical trials and practice with DRV/r plus TDF/FTC than with DRV/r plus ABC/3TC; therefore, DRV/r plus TDF/FTC is a Recommended regimen whereas DRV/r plus ABC/3TC is an Alternative regimen.

ACTG A5257, a large randomized open-label trial comparing ATV/r, DRV/r, and RAL, each given with TDF/FTC, found that all 3 regimens had similar virologic efficacy at week 96. A significantly higher proportion of patients in the ATV/r arm discontinued randomized treatment because of adverse events, mostly because of elevated indirect bilirubin/jaundice or gastrointestinal toxicities. Lipid changes were similar in the ATV/r and DRV/r arms.18
Choosing Among Integrase Strand Transfer Inhibitor Options

RAL plus TDF/FTC demonstrated comparable antiviral efficacy to EFV/TDF/FTC but with fewer drug related adverse effects and a more favorable lipid profile.12,16 RAL has fewer drug-drug interactions than boosted-PI, EVG/cobi/TDF/FTC, and EFV-based regimens, and is therefore easier to use in a patient who is receiving a complex medication regimen. One disadvantage of RAL is that it requires twice-daily dosing. There is more experience in clinical trials and practice with RAL plus TDF/FTC than with ABC/3TC; therefore, RAL plus TDF/FTC is a Recommended regimen whereas RAL plus ABC/3TC is an Alternative regimen.

EVG combined with cobi (a pharmaco-enhancer that boosts EVG concentrations) and TDF/FTC is available as a single-pill combination that is dosed once daily. EVG/cobi/TDF/FTC has comparable virologic activity to EFV/TDF/FTC19 or ATV/r plus TDF/FTC.20 The combination is well tolerated, with lower rates of neuropsychiatric adverse effects and rash than EFV/TDF/FTC. Cobi inhibits the tubular secretion of creatinine; as a result, soon after starting EVG/cobi/TDF/FTC, patients may have an increase in serum creatinine levels (average increase approximately 0.14 mg/dL; increase in most patients <0.4 mg/dL); levels usually stabilize soon after starting the drug. This regimen should be used only in patients with estimated creatinine clearance ≥70 mL/min. Because cobi, like PIs, inhibits the cytochrome p450 pathway (CYP3A4), combinations including this drug have more drug interactions than other INSTI-based regimens.

DTG, the most recently approved INSTI, was non-inferior to RAL-containing regimens21 and superior to DRV/r-22 and EFV-containing5 regimens in clinical trials, largely because of more discontinuations because of adverse events or other reasons in the comparator arms. DTG is dosed once daily when used for initial therapy and has fewer drug interactions than NNRTIs, PIs/r, and EVG/cobi/TDF/FTC—a potential advantage in patients on other medications that may interact with these drugs. Overall, DTG was well-tolerated in clinical trials. DTG decreases tubular secretion of creatinine, which causes small increases in serum creatinine in some patients soon after the drug is initiated. In clinical trials, no treatment-emergent resistance has been observed in treatment-naive patients who received DTG, suggesting that it may have a higher genetic barrier to resistance than RAL or EVG.

An antiretroviral regimen generally consists of two NRTIs plus one active drug from one of the following classes: NNRTI, PI (boosted with RTV), or INSTI. Selection of a regimen should be individualized on the basis of virologic efficacy, potential adverse effects, pill burden, dosing frequency, drug-drug interaction potential, a patient’s resistance test results and comorbid conditions, and cost. Table 7 lists the advantages and disadvantages of the ARV components listed below. Appendix B, Tables 1–6 provides dosing information. The regimens in each category are listed in alphabetical order. For more detailed recommendations on ARV choices and dosing in HIV-infected pregnant women, refer to the latest perinatal guidelines available at http://aidsinfo.nih.gov/guidelines.

ATV/r plus ABC/3TCa (AI)—only for patients who are HLA-B*5701 negative

Alternative Initial ART Regimen Options

Regimens that are effective and tolerable, but that have potential disadvantages when compared with the recommended regimens listed above or have less data from randomized clinical trials. An alternative regimen may be the preferred regimen for some patients.

PI-Based Regimens:

DRV/r plus ABC/3TCa (BII)—only for patients who are HLA-B*5701 negative

LPV/r (onceb or twice daily) plus ABC/3TCa(BI)—only for patients who are HLA-B*5701 negative

LPV/r (onceb or twice daily) plus TDF/FTCa (BI)

INSTI-Based Regimen:

RAL plus ABC/3TCa (BII)—only for patients who are HLA-B*5701 negative

a 3TC may be substituted for FTC or vice versa. The following combinations in the recommended list above are available as co-formulated fixed-dose combinations: ABC/3TC, EFV/TDF/FTC, EVG/cobi/TDF/FTC, LPV/r, RPV/TDF/FTC, and TDF/FTC.b Once daily LPV/r is not recommended for pregnant patients.

Several NRTIs, including ZDV, didanosine, and stavudine are no longer recommended as part of an initial ART regimen, primarily because of their toxicities. The Panel designates the fixed-dose combination of TDF/FTC as the Recommended NRTI backbone for most initial ART regimens. For patients who are HLA B*5701 negative, ABC/3TC is also Recommended when combined with DTG, regardless of pre-treatment HIV RNA level. It is also Recommended when combined with EFV or ATV/r, but only if the patient’s pre-treatment HIV RNA level is <100,000 copies/mL. (See Table 6 for recommendations and ratings for individual regimens). These recommendations are based on the virologic potency and durability, short- and long-term toxicity, and dosing convenience of these drugs.

Clinical Trials Comparing ABC/3TC to TDF/FTC

Several randomized controlled trials in ART-naive participants compared ABC/3TC to TDF/FTC, each with the same3,4,23 or a different third ARV drug (also see discussion in the DTG section).5 The virologic responses demonstrated in selected key studies are summarized below:

The ACTG 5202 study, a randomized controlled trial in more than 1800 participants, evaluated the efficacy and safety of ABC/3TC and TDF/FTC when each used in combination with either EFV or ATV/r.

Treatment randomization was stratified on the basis of a screening HIV RNA level <100,000 copies/mL or ≥100,000 copies/mL. HLA B*5701 testing was not required before study entry.

A Data Safety Monitoring Board recommended early termination of the ≥100,000 copies/mL stratification group because of a significantly shorter time to study-defined virologic failure in the ABC/3TC arm than in the TDF/FTC arm.3

This difference in time to virologic failure between arms was observed regardless of whether the third active drug was EFV or ATV/r.

There was no difference between ABC/3TC and TDF/FTC in time to virologic failure for participants who had plasma HIV RNA <100,000 copies/mL at screening.24

The ASSERT study compared open label ABC/3TC with TDF/FTC in 385 HLA B5701-negative, ART-naive patients; all participants also received EFV. The primary study endpoint was renal safety of the regimens. At week 48, the proportion of participants with HIV RNA <50 copies/mL was lower among ABC/3TC-treated participants than among TDF/FTC-treated participants.23

In the HEAT study, 688 participants received ABC/3TC or TDF/FTC in combination with once-daily LPV/r. Virologic efficacy was similar in the two study arms. In a subgroup analysis of patients with baseline HIV RNA ≥100,000 copies/mL, the proportion of participants who achieved HIV RNA <50 copies/mL at 96 weeks did not differ between the two regimens.4

Recommended Dual-Nucleoside Reverse Transcriptase Inhibitors

TDF/FTC

TDF, with either 3TC or FTC, has been studied in combination with EFV, RPV, several boosted PIs, EVG/cobi, RAL, and DTG in randomized clinical trials.12,15,21,25-31

Concomitant use of boosted PIs or cobi can increase TDF concentrations; studies have suggested a greater risk of renal dysfunction when TDF is used in PI- or cobi-based regimens.33,36-40

While initiation of all NRTI-containing regimens has been associated with a decrease in bone mineral density (BMD), the loss of BMD is greater with TDF-containing regimens. For example, in two randomized studies comparing TDF/FTC with ABC/3TC, participants receiving TDF/FTC experienced a significantly greater decline in bone mineral density than ABC/3TC-treated participants.41,42

Cases of osteomalacia associated with proximal renal tubulopathy have been reported with the use of TDF.43

Other Factors and Considerations:

TDF/FTC is available in fixed-drug combinations with EFV, EVG/cobi, and RPV, allowing the regimens to be administered as a single pill, given once daily.

Both TDF and FTC are active against hepatitis B virus (HBV). In patients with HIV/HBV coinfection, TDF/FTC should be used as the NRTI backbone of the ART regimen because the drugs have activity against both viruses (Also see HIV/HBV Coinfection section).

Panel’s Recommendation:

On the basis of clinical trial safety and efficacy data, long term experience in clinical practice, and the combination’s availability as a component of co-formulated products, the Panel considers TDF/FTC as a Recommended NRTI backbone for initial ART in treatment-naive patients (AI).

ABC/3TC

The dual nucleoside backbone of ABC and 3TC has been studied in combination with EFV, several PIs, and DTG in ART-naive patients.5,44-46

Adverse EffectsHypersensitivity Reactions:

Clinically suspected hypersensitivity reactions (HSRs) have been observed in 5% to 8% of individuals who started ABC in clinical trials conducted before the use of HLA-B*5701 testing. The risk of HSRs is highly associated with the presence of the HLA-B*5701 allele.47,48 HLA-B*5701 testing should precede use of ABC. ABC should not be given to patients who test positive for HLA-B*5701 and based on a positive test result, ABC hypersensitivity should be noted on a patient’s allergy list. Patients who are HLA-B*5701 negative are less likely to experience an HSR, but they should be counseled about the symptoms of the reaction. Patients who discontinue ABC because of a suspected HSR should never be re-challenged, regardless of their HLA-B*5701 status.

Cardiovascular Risk:

An association between ABC use and myocardial infarction (MI) was first reported in the D:A:D study. This large, multinational observational study group found that recent (within 6 months) or current use of ABC was associated with an increased risk of MI, particularly in participants with pre-existing cardiac risk factors.7,49

Since the D:A:D report, several studies have explored this association. Some studies have found an association;8,9,50,51 others, including an FDA meta-analysis of 26 randomized clinical trials that evaluated ABC, have found no association or a weak association.10,52-55

No consensus has been reached on the association between ABC use and MI risk or the mechanism for such an association.

Other Factors and Considerations:

ABC/3TC is available as a co-formulated tablet that can be given once daily with or without food.

ABC and 3TC are available separately in generic tablet formulations.

HLA-B*5701 testing should be performed before use of ABC and the drug should not be prescribed if a patient is found to be HLA-B*5701 positive.

ABC does not cause renal dysfunction and is a good substitute for TDF in patients with underlying renal dysfunction or who are at risk for renal effects. No dosage adjustment is required in patients with renal dysfunction.

Panel’s Recommendation:

The Panel recommends ABC/3TC as a dual NRTI, regardless of baseline HIV RNA, if it is prescribed with DTG (AI). EFV plus ABC/3TC (AI) and ATV/r plus ABC/3TC (AI) are classified as Recommended regimens only for patients with pre-treatment HIV RNA <100,000 copies/mL. As noted above, ABC should only be prescribed for patients who are tested negative for the HLA B*5701 allele (see Table 6 for more detailed recommendations on ABC/3TC use with other drugs).

Other Dual Nucleoside Reverse Transcriptase Inhibitors

ZDV/3TC

ZDV is associated with many adverse events, including bone marrow suppression, manifested by macrocytic anemia and/or neutropenia, GI toxicity, fatigue, and mitochondrial toxicity, including lactic acidosis/hepatic steatosis and lipoatrophy. ZDV/3TC is generally not recommended as a dual-NRTI option for ART-naive patients because ZDV/3TC has greater toxicity than TDF/FTC or ABC/3TC and requires twice daily dosing.

NNRTI-based regimens have demonstrated virologic potency and durability. The major disadvantages of currently available NNRTIs are the prevalence of NNRTI-resistant viral strains in ART-naive patients56,57 and the drugs’ low genetic barrier for the development of resistance. Resistance testing should be performed to guide therapy selection for ART-naive patients (see Drug-Resistance Testing). High level resistance to all NNRTIs (except ETR) may occur with a single mutation; cross resistance within the class is common. ETR has in vitro activity against some viral strains harboring mutations that confer resistance to DLV, EFV, and NVP.58 In RPV-treated patients, the presence of RPV resistance mutations at virologic failure may confer cross resistance to other NNRTIs, including ETR.59,60

The Panel recommends EFV with TDF/FTC as a recommended regimen regardless of a patient’s baseline HIV RNA and CD4 cell count (AI). RPV is also a Recommended NNRTI when used with TDF/FTC, but only for patients with pre-treatment HIV RNA <100,000 copies/mL and CD4 counts >200 cells/mm3 (AI).

NVP is no longer recommended as initial therapy because of the drug’s toxicities (serious and even fatal hepatic events and skin rash), especially in women and in patients with high CD4 counts, and also because of concerns about the drug’s efficacy in some clinical trials. However, patients doing well on NVP may continue the therapy. ETR at a dose of 200 mg twice daily is approved for use in treatment-experienced patients with virologic failure.61 In a small, randomized, double-blinded, placebo-controlled trial, ETR 400 mg once daily was compared with EFV 600 mg once daily (both in combination with 2 NRTIs) in treatment-naive participants (79 and 78 participants in the ETR and EFV arms, respectively). Virologic responses were comparable at 48 weeks.62 However, pending results from larger clinical trials, the Panel cannot recommend ETR as initial therapy.

EFV is an NNRTI approved for use in combination with 2-NRTIs for ART-naive patients.

Efficacy in Clinical Trials:
Large randomized, controlled trials and cohort studies in ART-naive patients have demonstrated potent and durable viral suppression in patients treated with EFV plus two NRTIs. In clinical trials, EFV-based regimens in ART-naive patients have demonstrated superiority or non-inferiority to several comparator regimens.

In ACTG 5142, EFV was superior to LPV/r, although drug resistance was more common after EFV failure than after LPV/r failure.63

In the 2NN study, compared to EFV, NVP did not meet non-inferiority criteria.64

In ACTG 5202, EFV was comparable to ATV/r when each given with either TDF/FTC or ABC/3TC.13

In the ECHO and THRIVE studies, EFV was non-inferior to RPV, with less virologic failure but more discontinuations due to adverse events. The virologic advantage of EFV was most notable in participants with pre-ART viral loads >100,000 copies/mL, and NRTI and NNRTI resistance was more frequent with RPV failure.14

In the GS 102 study, EFV/TDF/FTC was non-inferior to EVG/cobi/TDF/FTC.19

More recently, some regimens have demonstrated superiority to EFV, based primarily on fewer discontinuations because of adverse events:

In the SINGLE trial, a DTG-based regimen was superior to EFV at the primary endpoint of viral suppression at Week 48.5

In the STARTMRK trial, RAL was non-inferior to EFV at 48 weeks.12 RAL was superior to EFV at 4 and 5 years,16,31 in part because of more frequent discontinuations due to adverse events in the EFV group than in the RAL group.

In the open-label STaR trial, participants with baseline viral loads ≤100,000 copies/mL had higher rates of virologic suppression on RPV than on EFV.65

A recent multinational randomized placebo-controlled trial compared 600 mg (standard dose) with 400mg daily dosing of EFV, combined with TDF/FTC. At 48 weeks, EFV 400 mg was non-inferior to EFV 600mg.66 Study drug-related adverse events were less frequent in the EFV 400 mg group than in the 600 mg group. Although there were fewer self-reported CNS events in the 400 mg group, the two groups had similar rates of psychiatric events. Unlike the 600 mg dose of EFV, the 400 mg dose, is not approved for initial treatment and is not co-formulated into a single pill regimen.

Adverse Effects:

EFV can cause CNS side effects, such as abnormal dreams, dizziness, headache, and depression, which resolve over a period of days to weeks in most patients. However, more subtle, long-term neuropsychiatric effects can occur. A recent analysis of several comparative trials showed a higher rate of suicidality (i.e., reported suicidal ideation or attempted or completed suicide) among EFV-treated patients than among patients taking comparator regimens.67

EFV may cause elevation in LDL cholesterol and triglycerides.

Other Factors and Considerations:

EFV is formulated both as a single-drug tablet and in a fixed-dose combination tablet of EFV/TDF/FTC that allows for once daily dosing.

EFV is a substrate of CYP3A4 and an inducer of CYP3A4 and 2D6 and therefore may potentially interact with other drugs using the same pathways.

EFV has been associated with CNS birth defects in non-human primates, and cases of neural tube defects have been reported after first trimester exposure in humans.68 Alternative regimens should be considered in women who are planning to become pregnant or who are sexually active and not using effective contraception. Because the risk of neural tube defects is restricted to the first 5 to 6 weeks of pregnancy, before pregnancy is usually recognized, a suppressive EFV-based regimen can be continued in pregnant women who present for antenatal care in the first trimester (see Perinatal Guidelines).

Panel’s Recommendation:

On the basis of safety and efficacy data from numerous clinical trials and observational cohorts and long-term clinical experience with EFV, the Panel classifies EFV/TDF/FTC as a Recommended regimen for ART-naive patients (AI). EFV with ABC/3TC is Recommended only for patients with a pre-ART viral load of <100,000 copies/mL (see discussion in ABC/3TC section) (AI).

EFV at a reduced dose has not been studied in the United States. Until further data to support its use in the U.S. population is available; the Panel cannot recommend the use of reduced dose EFV.

RPV

RPV is an NNRTI approved for use in combination with NRTIs for ART-naive patients with pre-treatment viral loads <100,000 copies/mL.

Efficacy in Clinical Trials:
Two Phase 3 randomized, double-blinded clinical trials, ECHO and THRIVE, compared RPV and EFV, each combined with 2 NRTIs (80%, 15%, and 5% of participants received TDF/FTC, ZDV/3TC, and ABC/3TC respectively).14 At 96 weeks, the following findings were reported:

RPV was non-inferior to EFV overall.

Among participants with a pre-ART viral load >100,000 copies/mL, more RPV-treated than EFV-treated participants experienced virologic failure. Moreover, in this subgroup of participants with virologic failure, NNRTI and NRTI resistance was more frequently identified in those treated with RPV.

Among the RPV-treated participants, the rate of virologic failure was greater in those with pre-treatment CD4 counts <200 cells/mm3 than in those with CD4 counts ≥200 cells/mm3.

STaR, a Phase 3b, open-label study, compared the fixed-dose combinations of RPV/TDF/FTC and EFV/TDF/FTC in 786 treatment-naive patients. At 96 weeks, the following key findings were reported:65

RPV was non-inferior to EFV overall.

RPV was superior to EFV in patients with pre-ART viral loads ≤100,000 copies/mL and non-inferior in those with pre-ART viral loads >100,000 copies/mL. Virologic failure was more common in RPV-treated patients than in EFV-treated patients with pre-ART viral loads >500,000 copies/mL.

RPV is generally well tolerated. In the ECHO,THRIVE, and STaR trials, fewer CNS adverse events (e.g., abnormal dreams, dizziness, psychiatric side effects), skin rash, and dyslipidemia were reported in the RPV arms than the EFV arms, and fewer patients in the RPV arms discontinued therapy due to adverse events.

Other Factors and Considerations:

RPV is formulated both as an individual tablet and in a fixed-dose combination tablet with TDF/FTC. It is given as a once daily regimen, and must be administered with a meal (at least 400 kcal).

The oral drug absorption of RPV can be significantly reduced in the presence of acid-lowering agents. RPV is contraindicated in patients who are receiving proton pump inhibitors, and should be used with caution in those receiving H2 antagonists or antacids (see Drug Interactions section for dosing recommendations).

RPV is primarily metabolized in the liver by CYP3A enzyme; its plasma concentration may be affected in the presence of CYP3A inhibitors or inducers (see Drug Interactions section).

At higher than the approved dose of 25 mg, RPV may cause QTc interval prolongation. RPV should be used with caution when co-administered with a drug with known risk of Torsades de Pointes.

Panel’s Recommendation:

On the basis of clinical trial safety and efficacy data, the Panel considers RPV/TDF/FTC as a Recommended regimen, but only for ART-naive patients with pre-treatment viral load <100,000 copies/mL and CD4 count >200 cells/mm3 (AI). Data on RPV with ABC/3TC are insufficient to consider the combination either a Recommended or Alternative regimen.

Other Non-Nucleoside Reverse Transcriptase Inhibitors

NVP

NVP is approved for use in combination with 2-NRTIs for ART-naive patients. However, more serious toxicities, including severe and even fatal hepatic events, Stevens Johnson Syndrome, and toxic epidermal necrolysis, have been associated with NVP than with other NNRTIs. On the basis of the safety concerns and the availability of many other preferable options for initial therapy, the Panel no longer recommends initiation of NVP in ART-naive patients. Patients who are currently tolerating a suppressive NVP-based regimen may remain on the drug.

Protease Inhibitor-Based Regimens

Summary

FDA-approved PIs include ATV, DRV, FPV, indinavir (IDV), LPV/r, nelfinavir (NFV), RTV, SQV, and tipranavir (TPV). PI-based regimens (particularly with RTV-boosting) have demonstrated virologic potency and durability in treatment-naive patients, and a high genetic barrier to resistance. Few or no PI mutations are detected when a patient’s first PI-based regimen fails, which is not the case with NNRTI- and some INSTI-based regimens.70,71 All RTV-boosted PIs inhibit the cytochrome (CYP) 450 3A isoenzyme, which may lead to significant drug-drug interactions (see Drug Interaction section). Each PI has specific characteristics in terms of its virologic potency, adverse effect profile, and PK properties. The characteristics of Recommended and Alternative PIs are listed in Table 6 and Appendix B, Table 3.

A number of metabolic abnormalities, including dyslipidemia and insulin resistance, have been associated with PI use. The currently available PIs differ in their propensity to cause these metabolic complications, which also depends on the dose of RTV used as a PK boosting agent. Two large observational cohort studies suggest that LPV/r, IDV, FPV, or RTV-boosted FPV (FPV/r) may be associated with increased rates of MI or stroke.49,53 This association was not seen with ATV.72 These studies had too few patients receiving DRV/r to be included in the analysis.

Recommended PIs for use in ART-naive patients are those that have proven virologic efficacy, once daily dosing, a low pill count, good tolerability, and use a low dose of ritonavir (100 mg per day). On the basis of these criteria, the Panel considers once-daily ATV/r and DRV/r as Recommended PIs. LPV/r has a higher RTV dose and is associated with more metabolic complications and gastrointestinal side effects than ATV/r and DRV/r; for these reasons, it is considered an Alternative regimen. LPV/r remains as an Alternative PI/r because it is currently the only co-formulated boosted PI, it has extended experience in clinical trials and practice, and it has a role in treatment of HIV infection during pregnancy (see the Perinatal Guidelines for recommendations in pregnancy73). Compared to other PIs, FPV/r, unboosted ATV, and SQV/r have disadvantages such as greater pill burden, lower efficacy, or increased toxicity and thus are no longer included as Recommended or Alternative options.

Recommended Protease Inhibitor-Based Regimens (In Alphabetical Order)

ATV/r

Efficacy in Clinical Trials:

The CASTLE study compared once-daily ATV/r (300/100 mg) with twice-daily LPV/r (400/100 mg), each in combination with TDF/FTC, in 883 ART-naive participants. In this open-label, non-inferiority study, the 2 regimens showed similar virologic and CD4 responses at 48 weeks27 and at 96 weeks.74

The ACTG A5202 study compared open-label ATV/r and EFV, each given in combination with placebo-controlled TDF/FTC or ABC/3TC. Efficacy was similar in the ATV/r and EFV groups.13 In a separate analysis, women assigned to ATV/r were found to have a higher risk of virologic failure than women assigned to EFV or men assigned to ATV/r.17

In a study comparing ATV/r plus TDF/FTC to EVG/cobi/TDF/FTC, virologic suppression rates through 144 weeks were similar in the two groups.20

ACTG A5257, a large randomized open-label trial, compared ATV/r with DRV/r or RAL, each given with TDF/FTC. At week 96, all 3 regimens had similar virologic efficacy. However, a significantly higher proportion of patients in the ATV/r arm discontinued randomized treatment because of adverse events, mostly for elevated indirect bilirubin/jaundice or gastrointestinal toxicities. Lipid changes in participants in the ATV/r and DRV/r arms were similar. Bone mineral density decreased to a greater extent in participants in the ATV/r and DRV/r arms than in participants in the RAL arm.18

Adverse Effects:

In the CASTLE study, the participants randomized to ATV/r had fewer gastrointestinal toxicities and better lipid profiles than those who received LPV/r.

The main adverse effect associated with ATV/r is reversible indirect hyperbilirubinemia, with or without jaundice or scleral icterus, but without concomitant hepatic transaminase elevations.

Nephrolithiasis,75-77 nephrotoxicity,78 and cholelithiasis79 have also been reported in patients who received ATV, with or without RTV.

Other Factors and Considerations:

ATV/r is dosed once daily and with food.

ATV requires acidic gastric pH for dissolution. As a result, concomitant use of drugs that raise gastric pH (e.g., antacids, H2 antagonists, and particularly PPIs) may impair absorption of ATV. Table 18a provides recommendations for use of ATV/r with these agents.

ATV/r is a potent CYP3A4 inhibitor and may have significant interactions with other medications metabolized through this same pathway (see Drug Interactions section).

Panel’s Recommendation:

On the basis of clinical trial safety and efficacy data, the Panel classifies ATV/r plus TDF/FTC as a Recommended regimen for ART-naive participants regardless of pre-treatment HIV RNA (AI). ATV/r plus ABC/3TC is classified as a Recommended regimen, but only for patients whose pre-ART HIV RNA is <100,000 copies/mL (AI).

DRV/r

Efficacy in Clinical Trials:

The ARTEMIS study compared DRV/r (800/100 mg once daily) with LPV/r (800/200 mg once daily or 400/100 mg twice daily), both in combination with TDF/FTC, in a randomized, open-label, non-inferiority trial. The study enrolled 689 ART-naive participants. DRV/r was non-inferior to LPV/r at week 48,28 and superior at week 192.80 Among participants with baseline HIV RNA levels >100,000 copies/mL, virologic response rates were lower in the LPV/r arm than in the DRV/r arm.

The FLAMINGO study compared DRV/r with DTG, each in combination with two NRTIs, in 488 ART-naive participants. The rate of virologic suppression at week 48 was significantly greater among those who received DTG than in those who received DRV/r, largely because of more drug discontinuations in the DRV/r group.22

A small retrospective study that followed participants for 48 weeks suggested that DRV/r plus ABC/3TC may be effective in treatment-naive patients.81

The ACTG A5257 study showed similar virologic efficacy for DRV/r, ATV/r, and RAL, but more participants in the ATV/r group discontinued randomized treatment because of adverse events.18

Adverse Effects:

In the ARTEMIS Study, grades 2 to 4 adverse events, primarily diarrhea, were seen less frequently in DRV/r recipients than in LPV/r recipients.

Patients starting DRV/r may develop a skin rash, which is usually mild-to-moderately severe and self-limited. Treatment discontinuation is necessary on rare occasions when severe rash with fever or elevated transaminases occur.

Other Factors and Considerations:

DRV/r is administered once daily with food in treatment-naive patients.

DRV has a sulfonamide moiety, and should be used with caution in patients with severe sulfonamide allergies. In clinical trials, the incidence and severity of rash were similar in participants who did or did not have a history of sulfonamide allergy. Most patients with sulfonamide allergy are able to tolerate DRV.

DRV/r is a potent CYP3A4 inhibitor, and may lead to significant interactions with other medications metabolized through this same pathway (see Drug Interactions section).

Panel’s Recommendation:

On the basis of efficacy and safety data from clinical trials and clinical experience, the Panel classifies DRV/r with TDF/FTC as a Recommended regimen (AI). DRV/r with ABC/3TC is considered an Alternative regimen because there is has less efficacy data to support its use (BII).

Alternative Protease Inhibitor-Based Regimens

LPV/r

Efficacy in Clinical Trials:

A 7-year follow-up study of LPV/r and 2 NRTIs showed sustained virologic suppression in patients who were maintained on the originally assigned regimen.82

Results of clinical trials that compared LPV/r with ATV/r and DRV/r are discussed above.

In the ACTG 5142 study, at 96 weeks, a smaller proportion of patients who received LPV/r plus 2 NRTIs achieved viral suppression (HIV RNA <50 copies/mL) than those who received EFV plus 2 NRTIs. However, the CD4 cell response was greater with LPV/r, and there was less drug resistance associated with virologic failure.63

Adverse Effects:

In addition to diarrhea, major adverse effects of LPV/r include insulin resistance and hyperlipidemia, especially hypertriglyceridemia; these require pharmacologic management in some patients.

In the D:A:D and French observational cohorts, cumulative use of LPV/r was associated with a slightly increased risk of MI.49,53

In the D:A:D study, LPV/r use was also reported as an independent predictor of chronic renal impairment.78

Other Factors and Considerations:

LPV/r must be boosted with 200 mg/day of RTV and is associated with higher rates of GI side effects and hyperlipidemia than the Recommended PIs, which are boosted with 100 mg/day of RTV.

LPV/r can be given once or twice daily.

Once-daily dosing should not be used in pregnant women, especially during the third trimester, when LPV levels are expected to decline (see Perinatal Guidelines).

LPV/r is currently the only available co-formulated boosted PI. Co-formulation may lower a patient’s out-of-pocket costs by reducing the number of drug co-payments (see Cost Consideration section) and also prevent the patient from inadvertently not taking the RTV or the active PI.

Panel’s Recommendation:

On the basis of greater potential for adverse events and higher RTV dose and pill burden than ATV/r and DRV/r, the Panel recommends LPV/r plus TDF/FTC or LPV/r plus ABC/3TC as Alternative regimens (BI).

Integrase Strand Transfer Inhibitor-Based Regimens

Summary

Three INSTIs—DTG, EVG, and RAL—are currently approved for HIV-infected, ARV-naive patients. EVG is currently available as a component of a one-tablet once-daily complete regimen. All three agents are now classified as Recommended for use in ART-naive patients because regimens containing DTG, EVG, or RAL have proven virologic efficacy when compared to other Recommended regimens, and because the INSTIs are generally well tolerated.

Efficacy in Clinical Trials:
The efficacy of DTG in treatment-naive patients has been evaluated in three fully powered clinical trials, including two randomized double-blind clinical trials and one randomized open-label clinical trial. In these three trials, DTG-based regimens demonstrated either non-inferiority or superiority to a comparator INSTI, NNRTI, or PI-based regimen. The primary efficacy endpoint in all these clinical trials was the proportion of participants with plasma viral load <50 copies/mL.

The SPRING-2 trial compared DTG 50 mg once daily to RAL 400 mg twice daily, each in combination with investigator-selected NRTI of either ABC/3TC or TDF/FTC, in 822 participants. At week 96, DTG was non-inferior to RAL.21

The SINGLE trial compared DTG 50 mg once daily plus ABC/3TC to EFV/TDF/FTC in 833 participants. At week 48, DTG was superior to EFV, primarily because the study treatment discontinuation rate was higher in the EFV arm than in the DTG arm.5

The FLAMINGO study, a randomized open-label clinical trial, compared DTG 50 mg once daily to DRV/r 800 mg/100 mg once daily, each in combination with investigator-selected ABC/3TC or TDF/FTC. At week 48, DTG was superior to DRV/r because of higher rate of discontinuation in the DRV/r arm.22

Adverse Effects:

DTG is generally well-tolerated. The most common adverse reactions of moderate to severe intensity with an incidence of ≥2% in the clinical trials were insomnia and headache. Cases of hypersensitivity reactions were reported in <1% of trial participants.

Other Factors and Considerations:

DTG is given once daily, with or without food, in treatment-naive patients.

DTG decreases tubular secretion of creatinine without affecting glomerular function, with increases in serum creatinine observed within the first 4 weeks of treatment (mean change in serum creatinine of 0.11 mg/dL after 48 weeks).

On the basis of clinical trial data, the Panel categorizes DTG in combination with either ABC/3TC or TDF/FTC as a Recommended regimen in ART-naive patients (AI).

EVG

EVG is available only as a component of a four-drug, fixed-dose combination product containing EVG, cobi, TDF, and FTC (EVG/cobi/TDF/FTC). EVG/cobi/TDF/FTC is indicated as a one tablet once daily complete regimen for ARV-naive adult patients. cobi is a specific, potent CYP3A inhibitor that has no activity against HIV. It acts as a PK enhancer of EVG, which allows for once daily dosing of the combination.

Efficacy in Clinical Trials:
The efficacy of EVG/cobi/TDF/FTC in ARV-naive participants has been evaluated in two randomized, double-blind active-controlled trials.

At 144 weeks, EVG/cobi/TDF/FTC was non-inferior to fixed-dose EFV/TDF/FTC.19

EVG/cobi/TDF/FTC was also found to be non-inferior to a combination containing ATV/r plus TDF/FTC.20

Adverse Effects:

The most common adverse events reported with EVG/cobi/TDF/FTC were diarrhea, nausea, upper respiratory infection and headache.19,20

Other Factors and Considerations:

EVG is metabolized primarily by CYP3A enzymes; as a result, CYP3A inducers or inhibitors may alter EVG concentrations.

Because cobi inhibits CYP3A, it interacts with a number of medications that are metabolized by this enzyme (see Drug-Drug Interactions section).83

EVG plasma concentrations are lower when it is administered simultaneously with aluminum- or magnesium-containing antacids. Separate EVG/cobi/TDF/FTC and antacid administration by at least 2 hours.

Cobi inhibits active tubular secretion of creatinine, resulting in increases in serum creatinine and a reduction in estimated CrCl without reducing glomerular function.84

Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline while taking EVG/cobi/TDF/FTC should be closely monitored and evaluated for evidence of proximal renal tubulopathy.40

EVG/cobi/TDF/FTC is not recommended for patients with pre-treatment estimated CrCl <70 mL/min.40

At the time of virologic failure, INSTI-associated mutations were detected in some of EVG/cobi/TDF/FTC-treated patients whose therapy failed.19,20 These mutations conferred cross-resistance to RAL, with most retaining susceptibility to DTG.

Panel Recommendation:

On the basis of these factors, the Panel classifies EVG/cobi/FTC/TDF as a Recommended regimen in ART-naive patients (AI).

RAL

RAL was the first INSTI approved for use in both ARV-naive and ARV-experienced patients.

Efficacy in Clinical Trials:
The efficacy of RAL (with either TDF/FTC or ABC/3TC) has been evaluated in two randomized, double-blind active-controlled clinical trials enrolling ARV-naive participants and a small single-arm pilot trial. The primary endpoint in the clinical trials was plasma viral load <50 copies/mL.

STARTMRK compared RAL 400 mg twice daily to EFV 600 mg once daily, each in combination with the TDF/FTC. RAL was non-inferior to EFV at 48 weeks.12 RAL was superior to EFV at 4 and 5 years,16,31 in part because of more frequent discontinuations due to adverse events in the EFV group than in the RAL group.

In a small single-arm pilot trial of 35 participants who received a regimen of RAL in combination with ABC/3TC, 91% of participants had plasma viral loads <50 copies/mL at week 48.85

The SPRING-2 trial compared DTG 50 mg once daily to RAL 400 mg twice daily, each in combination with either investigator-selected ABC/3TC or TDF/FTC, in 822 participants. At week 96, DTG was non-inferior to RAL. In this trial, 164 participants (39 and 125 with baseline viral loads ≥100,000 copies/mL and <100,000 copies/mL, respectively) received RAL in combination with ABC/3TC. After 96 weeks, no difference in virologic response was apparent between the ABC/3TC or TDF/FTC groups when RAL was given as the third drug.21

ACTG A5257, a large randomized open-label trial, compared ATV/r with DRV/r or RAL, each given with TDF/FTC. At week 96, all 3 regimens had similar virologic efficacy. A significantly higher proportion of patients in the ATV/r arm discontinued randomized treatment because of adverse events, mostly for elevated indirect bilirubin/jaundice or gastrointestinal toxicities. Lipid changes in participants in the ATV/r and DRV/r arms were similar. Bone mineral density decreased to a greater extent in participants in the ATV/r and DRV/r arms than in participants in the RAL arm.18

Adverse Effects:

RAL use has been associated with creatine kinase elevations. Myositis and rhabdomyolysis have been reported.

Rare cases of severe skin reactions and systemic hypersensitivity reactions in patients who received RAL have been reported during post-marketing surveillance.86

Other Factors and Considerations:

RAL must be administered twice daily—a potential disadvantage when comparing RAL-based treatment with other Recommended regimens.

Co-administration of RAL with aluminum and/or magnesium-containing antacids can reduce absorption of RAL and is not recommended. Raltegravir may be co-administered with calcium carbonate-containing antacids.

RAL has a lower genetic barrier to resistance than RTV-boosted PIs.

Panel Recommendations:

On the basis of these data and the long-term clinical experience with RAL, the Panel considers RAL plus TDF/FTC as a Recommended regimen in ARV-naive patients (AI).

Given that few patients have received RAL plus ABC/3TC in clinical trials, and the availability of Recommended regimens with similar advantages, the Panel categorizes RAL plus ABC/3TC as an Alternative regimen (BII).

Other Antiretroviral Strategies for Initial Therapy When Abacavir or Tenofovir Cannot Be Used

All currently Recommended and Alternative regimens consist of two NRTIs plus a third active drug. This strategy, however, may not be possible or optimal in all patients. In some situations it may be necessary to avoid both TDF and ABC, such as in the case of a patient with pre-existing renal disease who is HLA B*5701 positive or at high risk of cardiovascular disease.

Based on these concerns, several clinical studies have evaluated strategies using initial regimens that avoid 2 NRTIs or the NRTI drug class altogether. Some of these studies were not fully powered to permit comparison with established regimens and one was a single-arm study using only a historical standard-of-care regimen as a control. At this point, the Panel does not recommend any of these strategies for initial therapy except in patients in whom both TDF and ABC are contraindicated. The major trials and their key results are summarized below.

PI/r plus NNRTI:

LPV/r plus EFV: In the ACTG 5142 trial, 757 ART-nave patients were randomly assigned to one of three regimens: an NRTI-sparing regimen of LPV/r plus EFV, EFV plus 2-NRTIs, or LPV/r plus 2-NRTIs. Although virologic responses in the LPV/r plus EFV and EFV plus 2-NRTI arms were comparable, the rates of drug resistance at treatment failure and hyperlipidemia were both higher in the NRTI-sparing group. This regimen also had an unacceptably high pill burden.63

PI/r (or Unboosted PI) plus INSTI:

DRV/r plus RAL: Three trials examined the role of DRV/r plus RAL in ART-naive patients.

NEAT/ANRS143 is a large randomized study (805 participants) comparing DRV/r plus RAL with DRV plus TDF/FTC in ARV-naive patients. At week 96, DRV/r plus RAL was non-inferior to DRV/r plus TDF/FTC in terms of the proportion of patients in each arm with virologic or clinical failure. Among those with baseline CD4 cell count <200/mm3, however, there were more failures in the RAL group. In patients with pre-treatment HIV RNA ≥100,000 copies/mL, there was a trend towards more failures in the RAL group.87

ACTG 5262 is a single-arm study in which 112 ART-naive patients received DRV/r once daily plus twice-daily RAL. There was a high rate of virologic failure (26%) at 48 weeks. Among the participants with pre-treatment HIV RNA levels >100,000 copies/mL, there was a higher rate of virologic failure and greater likelihood of emergence of INSTI-resistance at treatment failure.88

In the RADAR trial, 83 ART-naive participants were randomized to DRV/r plus RAL or DRV/r plus TDF/FTC. At 48 weeks, the rate of virologic suppression was significantly lower in the RAL group. There were more treatment discontinuations and virologic failures in the NRTI-sparing arm than in the TDF/FTC arm.89

LPV/r plus RAL: In the PROGRESS trial, 206 ART-naive patients were randomized to receive either LPV/r plus RAL or LPV/r plus TDF/FTC. LPV/r and RAL were given twice daily. At week 48, virologic responses to the regimens were similar. Compared to participants receiving TDF/FTC, those taking LPV/r plus RAL had greater changes in peripheral fat (but not trunk fat) and lipids but no changes in bone density (vs. declines in those receiving TDF/FTC). Participants in the TDF/FTC arm had greater reduction in estimated glomerular filtration rate from baseline. However, the regimen’s twice daily dosing requirement makes it less desirable for patients who prefer once daily therapy. In addition, the proportion of patients enrolled in this study with baseline HIV RNA >100,000 copies/mL was small.90

Unboosted ATV plus RAL: In the SPARTAN study, 94 ART-naive patients were assigned 2:1 to receive either an experimental regimen of twice daily RAL (400 mg BID) plus ATV (200 mg BID) or a standard TDF/FTC plus ATV/r treatment. While overall virologic responses were similar between arms, the twice daily ATV plus RAL arm had higher levels of virologic failure with resistance and jaundice than the TDF/FTC plus ATV/r group, prompting early termination of the study.91

PI/r plus CCR5 Antagonist:

DRV/r plus MVC: The MODERN Study was a fully-powered non-inferiority trial that compared DRV/r plus MVC to DRV/r plus TDF/FTC in 791 ART-naive patients with CCR5 tropic virus. At 48 weeks, significantly fewer patients in the MVC treatment group had HIV RNA <50 copies/mL, a difference that prompted the study’s Data and Safety Monitoring Board to recommend stopping the study (see http://clinicaltrials.gov/show/NCT01345630).

PI/r plus One NRTI:

LPV/r plus 3TC: In the GARDEL study, 426 ART-naive patients were randomized to receive twice-daily LPV/r plus either open-label 3TC (twice daily) or two NRTIs selected by the study investigators. At 48 weeks, a similar number of patients in each arm had HIV RNA <50 copies/mL, meeting the study’s non-inferiority criteria. The 3TC arm tended to be better tolerated than the 2 NRTI arm; notably, ZDV/3TC was the dual NRTI combination most commonly used.92

In summary, the aggregate results from most of the studies with NRTI-sparing regimens—with the exception of the NEAT ANRS 143 study, which has not yet been published—demonstrate that these initial strategies either have lower efficacy or more side effects than their standard-of-care treatment comparators without affording the benefit of reduced pill burden or dosing frequency. An additional concern is that the two most favorable outcomes in studies thus far were seen with twice-daily LPV/r based regimens (in the PROGRESS and GARDEL trials); LPV/r is not considered a Recommended initial regimen because of its unfavorable lipid, tolerability and pill burden characteristics as compared to ATV/r and DRV/r. PI/r monotherapy has been studied as an NRTI-sparing strategy, but mainly in the setting of regimen simplification in patients who have achieved viral suppression on an initial combination ART regimen. The results of clinical trials evaluating these regimens are discussed in the Regimen Switching in the Setting of Virologic Suppression section. As stated earlier, at this point, the Panel does not recommend any of these strategies for initial therapy except in patients in whom both TDF and ABC are contraindicated.

Inferior virologic responses in patients with baseline HIV RNA ≥100,000 copies/mL when given with EFV or ATV/r as compared with TDF/FTC in ACTG 5202 study. This difference not seen when ABC/3TC was used in combination with DTG.

Requires HLA-B*5701 testing before use

Potential for ABC HSR in patients with HLA-B*5701 allele

ABC use has been associated with cardiac events in some but not all observational studies.

TDF/FTC

Better virologic responses than with ABC/3TC in patients with baseline viral load ≥100,000 copies/mL when combined with ATV/r or EFV

May have lower genetic barrier to resistance than seen with boosted PI- or DTG-based regimens

Food requirement

RAL

Longest post marketing experience in comparison to other INSTIs

No food requirement

No CYP3A4 interactions

Twice-daily dosing

May have lower genetic barrier to resistance than seen with boosted PI- or DTG-based regimens

Increase in creatine kinase, myopathy, and rhabdomyolysis have been reported.

Rare cases of severe hypersensitivity reactions (including SJS and TEN) have been reported.

Metal-containing antacids can reduce the absorption of RAL. Co-administration of RAL with Al+++ and/or Mg++-containing antacids is not recommended. RAL may be co-administered with CaCO3 containing antacids. (See dosing recommendations in Table 18d.)

The SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22(14):F17-24. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18753925.

Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.